Cordycepin stimulates autophagy in macrophages and prevents atherosclerotic plaque formation in ApoE-/- mice

// Xin Li 1, * , Yue Zhou 1, * , Xue Zhang 1 , Xiaoxue Cao 1 , Chongming Wu 1 and Peng Guo 1 1 Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, P.R. China * These authors have contributed equally to this work Correspondence to: Chongming Wu, email: cmwu@implad.ac.cn Peng Guo, email: pguo@implad.ac.cn Keywords: cordycepin, atherosclerosis, foam cell, autophagy, AMPK Received: July 27, 2017 Accepted: September 21, 2017 Published: October 16, 2017 ABSTRACT Autophagy in macrophages plays a key role in the pathogenesis and progression of atherosclerosis and has become a potential therapeutic target. Here we show that cordycepin (Cpn), a natural derivative of adenosine, markedly reduced atherosclerotic plaque and ameliorated associated symptoms such as dyslipidemia, hyperglycemia and inflammation in ApoE -/- mice. Supplementation of Cpn dose-dependently inhibited oxLDL-elicited foam cell formation and modulated intracellular cholesterol homeostasis by inhibiting cholesterol uptake and promoting cholesterol efflux in RAW264.7 macrophages. Notably, Cpn exhibited significant stimulating effect on macrophage autophagy, as estimated by western blotting, immunofluorescent staining and autophagic vacuoles observation by transmission electron microscopy. The inhibitive effects of Cpn on foam cell formation were dramatically deteriorated in the presence of various autophagy inhibitors, suggesting that autophagy participate, at least in part, in the atheroprotective role of Cpn. Further investigations using different autophagy inhibitors and specific siRNAs for AMP-activated protein kinase (AMPK) gamma1 subunit indicated that Cpn may stimulate macrophage autophagy through AMPK-mTOR pathway. Together, our results demonstrated Cpn as a potential therapeutic agent for the prevention and treatment of atherosclerosis, and the autophagic activity presents a novel mechanism for Cpn-mediated atheroprotection.